Tissue in a living creature is continually repairing and regenerating. Normally this repair and regeneration occurs naturally without any adverse effect. However, in certain circumstances, for example following severe tissue damage or inflammation, the repair and regeneration of the tissue can become excessive, leading to fibrosis. Fibrosis is the presence of excessive connective tissue and can generically be referred to as scarring.
Within the gastrointestinal tract (GIT), fibrosis can be caused by various diseases especially inflammatory- or ischemic-induced diseases, for example cystic fibrosis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, coeliac diseases, proctitis, gastrointestinal graft-versus-host disease (GIGVHD), ischemic bowel diseases, necrotizing enterocolitis, and irritable bowel syndrome.
Patients suffering from these chronic conditions often have the added complication of intestinal fibrosis. Fibrosis causes strictures and obstruction of the intestine that require surgery to remove along with portions of the bowel. The therapeutic problems caused by bowel wall fibrosis are common: for example, about 75% of all patients with Crohn's disease have to undergo surgery at least once during the course of their disease. Such fibrosis is a long term complication in inflammatory bowel disease in general, including where therapies control the symptoms but the underlying disease continues to be active and leads to tissue damage in the form of fibrosis.
In contrast to anti-inflammatory treatment, little therapeutic progress has been made with respect to intestinal fibrosis. Current preventive attempts therefore rest primarily on long-term anti-inflammatory treatment. However, this mainly anti-inflammatory approach is often ineffective, leading to surgery and stricturoplasty, which remain the major treatment methods for intestinal fibrosis and, despite the major therapeutic advances in the treatment of Crohn's disease, the incidence of stricture formation in Crohn's disease has not markedly changed. Such observations imply that control of inflammation at the clinical level does not equate with control of fibrogenesis. Unfortunately, even the surgical approach is often only associated with short-term resolution of symptoms, as strictures tend to recur. For further information on intestinal fibrosis see “Wound Healing and Fibrosis in Intestinal Disease”, F Rieder et al., Gut 2007; 56: 130-139 and “Intestinal fibrosis in IBD—a dynamic, multifactorial process”, F Rieder et al., Nat. Rev. Gastroenterol. Hepatol. 6, 228-235 (2009).
There are, therefore, currently no satisfactory treatments for intestinal fibrosis. At present, the only option other than surgery to treat the obstructions and strictures caused by fibrosis is endoscopic balloon dilation.
WO 2012/069658 discloses a method of administering to a warm-blooded animal a formulation to treat, or delay the progression of, a fibrotic intestinal disorder, or of maintenance therapy of an animal which has suffered from or is suffering from a fibrotic intestinal disorder, which method comprises orally administering to the animal simultaneously, sequentially or separately an immunosuppressant and a hydroxylase inhibitor. The actives may be in a pharmaceutical composition which comprises a hydrophobic phase in which the immunosuppressant is dissolved. For example, the composition may be a multiple minibead composition wherein the immunosuppressant and the hydroxylase inhibitor are contained in the minibeads, each minibead comprising a water-soluble polymer matrix material and, dispersed within the matrix material, the hydrophobic phase. In an embodiment, the immunosuppressant is cyclosporin A and the hydroxylase inhibitor is hydralazine, in which case the hydralazine may be comprised in the matrix material of such minibeads.
Budesonide (16, 17-butylidendioxy-11β, 21-dihydroxy-1,4-pregnadien-3,20-dione) is a topical corticosteroid characterized by potent local anti-inflammatory activity, and was initially introduced for the treatment of asthma and rhinitis. Due to an extensive first-pass elimination its systemic bioavailability is only 10-15% compared with other corticosteroid formulations, thus, improved safety and tolerability might be anticipated (Navarro F et al., Treatment of inflammatory bowel disease: safety and tolerability issues. Am J Gastroenterol 2003; 98 (12(Suppl): S18-23).
Orally administered budesonide (sold as Entocort®) is indicated for the treatment and maintenance therapy of Crohn's disease involving the ileum and/or the ascending colon. It is proposed also to use a budesonide formulation for the treatment of ulcerative colitis (G R D'Haens et al., J Crohn's Colitis (2010) 4, 153-460). Such uses of budesonide are based on the compound's anti-inflammatory activity and the compound is not indicated for the treatment of intestinal fibrosis.
A new extended release budesonide formulation, namely MMX®-budesonide tablets, has been made which is designed to release budesonide at a controlled rate throughout the whole colon for the oral treatment of inflammatory bowel diseases (IBD). See Brunner M et al., Br J Clin Pharmacol 61:1, 31-38.
All of the above-mentioned publications, and all other publications mentioned in this specification, are incorporated herein by reference.